This study is in response to the mission of the National Institute of Biomedical Imaging and Bioengineering ("Research and development of nano-scale technologies for biomedical imaging") and the National Cancer Institute ("Early detection of disease using imaging"). The inflammatory immune response in breast cancer stroma has been identified as a major promoting factor for breast cancer carcinogenesis and progression. Histopathologic evaluations showed that the presence and quantity of tumor-associated macrophages (TAM) in breast cancer stroma correlates strongly with tumor aggressiveness and poor outcome. The major goal of our project is to develop a new and non-invasive diagnostic assay for selective targeting and visualization of TAM in breast cancer, based on magnetic resonance (MR) imaging and the FDA-approved iron oxide nanoparticle compound ferumoxytol (FerahemeTM, hydrodynamic diameter 28-32 nm). Realization of this goal will lead to the development of a novel and non- invasive assay for TAM infiltration in breast cancer stroma, which could be utilized to predict tumor progression and poor outcome in breast cancer patients and assign these patients to individualized therapeutic options. Of note, only few nanoparticle-based drugs are in a stage of development where they can be applied in a clinical setting. Feraheme is FDA-approved for the treatment of iron deficiency and would be in principle applicable for "off label" translational applications in patients with breast cancer. The imaging approach relies on the tumor microvascular permeability, interstitial retention and TAM phagocytosis of intravenously administered ferumoxytol in breast cancers. The phagocytosed nanoparticles in TAM cause alterations of local magnetic fields, which can be detected as areas of decreased signal intensity on "delayed" T2-weighted MR images, 24 hours after intravenous nanoparticle administration. In a step-by-step approach, we will first compare the quantitative ferumoxytol uptake and MR signal enhancement of breast cancer cells and different populations of TAM in vitro, then correlate the ferumoxytol-enhancement of breast cancers on MR images with the quantity of TAM in the tumor tissue in animal models of breast cancer and finally correlate breast cancer ferumoxytol uptake and MR enhancement in vivo with tumor grade on histopathology. By exploiting a novel imaging technique that provides a non-invasive measure for breast cancer immune response and aggressiveness, we anticipate to significantly improving our ability to characterize breast cancer biology in vivo, to assign patients to individualized therapeutic options, develop and monitor new anti-inflammatory therapies and ultimately, improve long term outcomes of patients with breast cancer. PUBLIC HEALTH RELEVANCE: Tumor associated macrophages are immune-system cells in breast cancer tissue, which correlate strongly with more aggressive tumors and worse long term prognosis. Currently, tumor aggressiveness is evaluated by histology and immunochemistry, both of which require tumor tissue either from a biopsy or surgery. The goal of this project is to investigate the ability of a non-invasive imaging method, based on magnetic resonance imaging and the FDA approved nanoparticle ferumoxytol, to detect tumor associated macrophages in breast cancer. This could be used to assign patients with more aggressive tumors to individualized therapeutic options, develop and monitor new anti-inflammatory therapies and ultimately improve long term outcomes.